Type I Diabetes:

Insulin Dependent Diabetes Mellitus

Mechanism

Insulin Dependent Diabetes Mellitus (IDDM) is a type of organ specific autoimmune disorder characterized by the destruction of pancreatic beta cells by cytotoxic T cells. About 1,000 insulin secreting beta cells are located in a spherical cluster called an islet of Langerhans. These islets make up 1-2% of pancreatic mass, are scattered throughout the pancreas, and contain other secreting cells.* The autoimmune attack on the beta-cells, compromises the production of insulin and thereby the functions associated with insulin.

The attack on beta-cells is initiated by activated cytotoxic T-lymphocytes (CTLs) that target specific islets for lysis (destruction). The CTL activity triggers the release of cytokines (immune hormonal messengers) which in turn stimulate the proliferation of activated macrophages and autoantibodies that are attracted to the site of inflammation (immune activation). The autoantibodies, together with complement-mediated lysis as well as macrophage and CTL activity, are responsible for the overall destruction of pancreatic tissue and create the ensuing pathology.

The question remains, which autoantigens trigger the immune system activation? Studies have revealed several autoantigens that can be associated with the precipitation of the autoimmune response. Many of these are connected to the secretion granules, such as beta-grabule antigen and carboxypeptidase. Two insulin secretory organelles have also be identified. Interestingly, prediabetics (people with early and underdeveloped signs of diabetes)* have elevated levels of insulin autoantibodies (IAAs).

Genetics seems to play a large role in the autoimmune aspect. It is suspected that autoimmunity occurs when a patient is genetically susceptible (encoded in the same area as HLA alleles). 'Superantigens' are a theorized result of certain alleles; superantigens activate large amounts of T-cells (much more than normal). As the term 'genetic susceptibility' indicates, the patient is merely at risk because of genes and there are environmental factors at work as well (such as viral infection or direct trauma).**

***

*Eisenbarth, GS. Primer: Imunology/Autoimmunity. from Eisenbarth, GS & Lafferty, KJ. (Eds.) Oxford University Press: New York. 1996. Type I Diabetes: Molecular, Cellular, and Clinical Immunology.

*Pietropaolo, M & Babu, S. The Targe Organ: Embryology, Biochemisty, and Physiology. from Eisenbarth, GS & Lafferty, KJ. (Eds.) Oxford University Press: New York.1996. Type I Diabetes: Molecular, Cellular, and Clinical Immunology.

***Diabetes and Gene Therapy: Prospects of Gene Therapy for Autoimmune Diabetes

Pathology


The the damage done by the autoimmune attack has important physiological consequences. The destruction of beta cells compromises an individual's ability to respond to changing levels of glucose in the blood because insulin cannot be produced. Insulin has important functions in the metabolism of carbohydrate, fatty acids and amino acids. When these molecules enter the blood stream in their absorbtive state, insulin catalyzes their cellular uptake and synthesis into glycogen, triglycerides and proteins.

With regards to glucose regulation, insulin has four main functions, depending on glucose levels and cellular needs:

1. Insulin opens the glucose transport proteins (GLUT 1-5) allowing for passive diffusion of glucose into cells.

2. Insulin stimulates formation of glycogen from glucose (glycogenesis) for the purpose of storing energy in cells.

3. Insulin inhibits the breakdown of glycogen to glucose (glycogenolysis) favoring glycogen storage and reducing glucose output by the liver.

4. Glucose prevents the breakdown of glucose from amino acids (gluconeogenesis) by reducing the amount of amino acids available to the liver as well as blocking hepatic glucogeneic enzymes.

By promoting protein synthesis, insulin enhances the activity of cellular mechanisms. Glucose consumption increases and blood glucose decreases. Insulin is the only hormone capable of downregulating blood sugar, and thus patients suffering from IDDM experience acute periods of hyperglycemia (too much glucose in the blood). Although the blood is rich in glucose, IDDM patients are starved for energy because cells are incapable using any of the glucose without insulin (similar to torture described in Dante's Inferno).

Complications

IDDM results in a cascade of complications which, if left untreated, lead to death.

Without appropriate amounts of insulin, the body is unable to maintain proper metabolism. Other regulatory pathways compensate by breaking down triglyceride stores into fatty acids. This process results in futher elevating blood glucose levels and the production of ketones (toxic by-products) This results in metabolic acidosis (ketoacidosis) and hyperglycemia and can easily lead to a diabetic coma.

Hyperglycemia leads to glucose in the urine because there is too much for effective kidney reabsorbtion. The presence of glucose in urine creates an osmotic gradient which pulls water from the blood. The blood volume is thus decreased leading to decreased cereberal blood flow, and peripheral circulatory failure. In turn this can lead to a diabetic coma (passing out until blood flow is sufficiently reinstated), kidney failure, loss of function in peripheral limbs and organs (foot sores, gum decay, amputation, blindness), and death.

Prolonged lack of protein synthesis and increased protein degradation leads to muscle wasting and weight loss. It also causes a decrease glucose consumption thus aggravating hyperglycemic complications. Hyperglycemia is treated with a dose of insulin - whether by shot, pump, or diffusion from the peritoneal cavity.

It is also possible to have too much insulin in one's system (hypoglycemia or low blood sugar). This is when too much of a person's circulating glucose has been removed by an overdose of insulin. This is treated simply with intake of sugar or carbohydrates.

Despite the efficacy of insulin in treating acute complications like a diabetic coma, long term complications typically occur 15 - 20 years after the initial diagnosis. These long term complications (heart disease, strokes, kidney failure, amputation, etc) are serious and the result of imperfect treatment of diabetes. Although insulin infusions are effective in treating hyperglcemia, there is still a significant lag time between the need for insulin and its administration. This lag time causes diabetic patients to be exposed to high levels of blood glucose. Vascular damage caused by regular exposure of tissue to elevated blood glucose and decreased peripheral circulation are thought to be the catalyst for all of the prior mentioned complications. It is very difficult to exactly replicate the body's natural reaction to glucose (some advances are being made with glucose sensors). This deficiency in insulin treatment is the problem driving the development of therapies that more closely mimic the natural release of insulin in response to varying glucose levels.